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J. Biol. Chem., Vol. 279, Issue 29, 30844-30849, July 16, 2004

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Casein Kinase 1 Interacts with Retinoid X Receptor and Interferes with Agonist-induced Apoptosis^*

Yi Zhao, Suofu Qin, Larissa I. Atangan, Yanira Molina, Yumiko Okawa, Hieu T. Arpawong, Corine Ghosn, Jia-Hao Xiao, Vidyasagar Vuligonda¶, Geoffrey Brown||, and Roshantha A. S. Chandraratna¶**

From the Retinoid Research, Departments of Biology and ^¶Chemistry, Allergan Inc., Irvine, California 92612 and ^||Division of Immunity and Infection, University of Birmingham Medical School, Edgbaston, Birmingham B15 2TT, United Kingdom

Agonists of retinoid X receptors (RXRs), which include the natural 9-cis-retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anti-cancer effects of RXR agonists remain unclear. Here, we show that a novel pro-apoptotic pathway that is induced by RXR agonist is negatively regulated by casein kinase 1 (CK1). CK1 associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an RXR agonist to recruit CK1 to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1 in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1 can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1 may enhance the anti-cancer effects of RXR agonists.

Received for publication, April 27, 2004 , and in revised form, May 5, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Allergan Inc., Retinoid Research, 2525 Dupont Dr., Irvine, CA 92612. E-mail: zhao_yi{at}allergan.com. ^**To whom correspondence may be addressed: Allergan Inc., Retinoid Research, 2525 Dupont Dr., Irvine, CA 92612. E-mail: chandraratna_rosh{at}allergan.com.

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